GABA ameliorates diabetic kidney disease-induced podocyte injury via JAML-FPR2 axis-mediated suppression of macrophage infiltration.

This study demonstrates that gamma-aminobutyric acid (GABA) ameliorates diabetic kidney disease (DKD) by modulating macrophage-driven inflammation and podocyte injury through the JAML/FPR2 signaling axis. In streptozotocin (STZ)-induced DKD mice, GABA administration significantly improved renal function by reducing serum creatinine, urea nitrogen, 24-hour urine protein, attenuated glomerular hypertrophy/mesangial expansion, and suppressed pro-inflammatory cytokine production (TNF-α, IL-1β, iNOS) in renal tissue and serum. GABA inhibited glomerular macrophage infiltration (CD68+ cells) and M1 polarization while mitigating renal apoptosis and podocyte injury by restoring nephrin and podocin. In a high glucose (HG)-stimulated macrophage-podocyte co-culture model, GABA reduced HG-induced podocyte apoptosis in a macrophage ratio-dependent manner by reversing M1 polarization and inflammatory cytokine overproduction. Mechanistically, GABA normalized DKD-elevated JAML expression in renal tissues and podocytes, while JAML overexpression abolished GABA's renoprotective effects by reactivating inflammation, macrophage recruitment, and podocyte apoptosis. Co-IP confirmed JAML interacted with receptor formyl peptide receptor 2 (FPR2), which mediated DKD-driven macrophage infiltration, as FPR2 knockdown abrogated JAML-induced CD68+ cell accumulation. Collectively, GABA alleviated DKD progression by disrupting the JAML/FPR2 axis to suppress macrophage-mediated inflammation and podocyte injury, highlighting its therapeutic potential for diabetic kidney disease.